TGF-β downregulates c-myc via another pathway

Transforming growth factor β (TGF-β) inhibits the growth of many cell types and loss of TGF-β sensitivity has been implicated in tumorigenesis. Downregulation of c-myc is a crucial event in inhibition of growth induced by TGF-β and is frequently impaired in cancer cells. Resistance to TGF-β can be the result of the obvious mutations, either in its receptor or in direct downstream mediators (i.e. SMADs). However, resistance exists in several cells harboring neither of these mutations. TGF-β induces G1 arrest by its effects on the retinoblastoma (Rb)–E2F pathway, with c-myc among its targets. In accordance with this, overexpression of c-myc can abrogate TGF-β-induced arrest in keratinocytes and sustain proliferation in Mv1Lu cells in the presence of TGF-β. However, dephosphorylation of Rb family proteins requires several hours, whereas TGF-β downregulates c-myc mRNA within one hour.Yagi et al. [1xSee all References][1] now demonstrate that TGF-β downregulates c-myc independently from the Rb pathway. They identified TGF-β-responsive elements in the c-myc promoter. This element is a complex of the TGF-β1 inhibitory element (TIE), which was originally identified in the Transin/Stromelysin promoter, and an E2F site responsible for transcriptional activation of the c-myc promoter. SMAD and E2F-4 directly bound to the element (TIE–E2F) and suppressed c-myc promoter activity. Some repressors of transcription from the c-myc promoter act by reducing E2F binding activity to the E2F element. Interestingly, Yagi et al. show that TGF-β-mediated c-myc repression occurred without affecting E2F-4 binding, suggesting that molecules other than E2F-4 are responsible for transcriptional activation of c-myc. TGF-β-induced repression would then occur by competing for these c-myc activators. The authors suggest this might be p300 but fail to show direct p300 binding to the TIE–E2F. Further studies are needed to determine whether TGF-β signaling suppresses c-myc promoter activity by dissociating p300 from E2F-4.The authors also show that transcriptional regulation via TIE–E2F of the c-myc promoter was selectively impaired in cancer cell lines, which suggests that this is a commonly used and important mechanism in carcinogenesis. Given the fact that c-myc is one of the most potent regulators of cell-cycle progression in higher eukaryotes and is deregulated in 15% of all human tumors, this opens up a new route to the understanding of regulation of the autonomous cancer cell growth.